Rw. Vazquez et Re. Oswald, Identification of a new amino acid residue capable of modulating agonist efficacy at the homomeric nicotinic acetylcholine receptor, alpha 7, MOLEC PHARM, 55(1), 1999, pp. 1-7
Neuronal nicotinic receptors (nAChRs) have been implicated in pathology ass
ociated with neurological diseases and aberrant cognitive states such as ad
diction and schizophrenia. The design of subtype-specific cholinergic drugs
is dependent on identification of key amino acids that play a significant
role in determining subunit-specific agonist efficacy. 1,1-Dimethyl-4-pheny
lpiperazinium (DMPP) and a series of piperazium (PIP)-derived cholinergic a
gonists (1,1 dimethyl-4-acetylpiperizinium iodide, EthylPIP, PropylPIP, and
ButylPIP) were used to identify a site (position 84) in homomeric neuronal
nAChRs, which is a partial determinant of pharmacological specificity. In
contrast to absolutely conserved amino acids within the nicotinic superfami
ly, the amino acid in position 84 can be polar or nonpolar. The addition of
one methylene to PropylPIP to form ButylPIP eliminated channel activation
of but not binding to the chick alpha 7 homomeric nAChR (leucine in positio
n 84). In rat alpha 7 (glutamine in position 84), ButylPIP was an agonist.
1,l-Dimethyl-4-phenylpiperazinium, a structural analog of ButylPIP, activat
es the rat alpha 7 but is a weak partial agonist of the chick alpha 7. Muta
tion of the chick alpha 7 (L84Q) restored activation by ButylPIP, and the c
orresponding mutation in rat alpha 7 (Q84L) abolished activation by ButylPI
P. These mutations had moderate effects on the apparent affinity for acetyl
choline, increasing its affinity for chick alpha 7 and decreasing it for ra
t alpha 7. Thus, the amino acid in position 84 (a residue on the periphery
of the highly conserved loop A of the cys-loop superfamily of receptors) ca
n potentially be exploited to produce subtype-specific drugs and can provid
e insights into the structure of the binding domain.